tbuckley/cabot-search huggingface dataset:
Abstract 4587: Vascular-derived signature imprinted by tumor microenvironment-dependent transcriptional memory predicts colon cancer prognosis
Authors: Elisabeth Naschberger, Maximilian Fuchs, Nicholas Dickel, Meik Kunz, Charles G. Anchang, Richard Demmler, Bernt Popp, Arif B. Ekici, Steffen Uebe, Carol I. Geppert, Claudia Günther, Susanne Merkel, Vera S. Schellerer, Michael Stürzl
Journal: Cancer Research (2023)

Abstract Background: Antiangiogenic therapy is part of the guideline therapy of colorectal cancer (CRC). Surprisingly, the impact of the tumor microenvironment (TME) on tumor vessel endothelial cells (TECs) is largely unclear. The aim of this study was to investigate the presence of a TME-dependent transcriptional memory in TECs isolated from patients and to exploit it to retrieve signatures that characterize TECs in different intratumoral TMEs with impact on patient outcome. Methods: ECs from tumor and normal colon tissues, PBMCs and tumor cells were isolated from CRC patients with different prognostic TMEs. Cells were analyzed by qPCR, immunocytochemistry and multi-omics (transcriptomics, EPICmethylation chips, exome sequencing). Integrative bioinformatics was used to identify TME-dependent memory genes predicting prognosis and scRNASeq to validate endothelial gene expression in CRC tissues. Results: Ultrapure TECs were isolated from CRC with different prognostic TMEs (Th1 vs. non-Th1) and systematically compared by multi-omics. A transcriptional memory differentiating the respective TEC groups was identified. This in vivo imprinted transcriptional memory was preferentially regulated by epigenetic DNA methylation but not by genomic alterations and was different from an in vitro primed transcriptional memory to IFN-γ. Moreover, it was specific for TECs and not observed in CAFs. With integrative bioinformatics a TME-dependent memory signature was extracted and its expression in TECs in CRC tissues was confirmed by scRNASeq. Notably, the identified signature predicted the prognosis of CRC patients. Conclusion: We identified a tumor vessel-derived TME-dependent transcriptional memory signature that was manifested by epigenetic mechanisms and allowed tumor vessel-based prediction of CRC patients prognosis. Citation Format: Elisabeth Naschberger, Maximilian Fuchs, Nicholas Dickel, Meik Kunz, Charles G. Anchang, Richard Demmler, Bernt Popp, Arif B. Ekici, Steffen Uebe, Carol I. Geppert, Claudia Günther, Susanne Merkel, Vera S. Schellerer, Michael Stürzl. Vascular-derived signature imprinted by tumor microenvironment-dependent transcriptional memory predicts colon cancer prognosis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4587.
Abstract 5012: Characterizing the functional significance of PDGFRAK385I and PDGFRAK385L extracellular domain mutations in the newly defined myxoid glioneuronal tumor
Authors: Catherine Z. Beach, Romel Somwar, Matthew D. Wood, Monika A. Davare
Journal: Cancer Research (2023)

Abstract In 2021, the World Health Organization (WHO) approved new diagnostic guidelines that stratify central nervous system (CNS) tumors based on molecular, transcriptomic, and epigenetic analysis instead of relying solely on phenotypic characterization and added twenty-two new CNS tumor entities based on these guidelines. Our focus is on one of these newly defined entities—myxoid glioneuronal tumors—a slow growing, mucinous glial tumor defined by a pathognomonic dinucleotide substitution in the extracellular domain of PDGFRA p.K385I/L. PDGFRA p.K385I/L remains a variant of unknown significance, however, constitutive activation of PDGFRA is well established as a pharmacologically actionable, oncogenic driver present in a variety of tumor types. Here we report the functional characterization of PDGFRAK385I and PDGFRAK385L by assessing transforming potential using Ba/F3 cells and immortalized human astrocytes. Our results demonstrate that both p.K385I and K385L substitutions are oncogenic, driving cytokine-independent Ba/F3 cell growth and anchorage-independent colony formation. Western blot analysis of downstream cellular signaling pathways in the absence of PDGF-ligand further confirm the activating nature of these mutations, showing robust phosphorylation of PDGFRA and constitutive phosphorylation of downstream signaling effectors ERK1/2, SHP2, and STAT3. To assess whether PDGFRAK385I and PDGFRAK385L are pharmacologically actionable, we tested multiple tyrosine kinase inhibitors with known activity against PDGFRA aberrant cancers using our mutant-transformed PDGFRA Ba/F3 cells. We found that the PDGFRAK385I and PDGFRAK385L mutants were sensitive to inhibitors axitinib, AZD-3229, and avapritinib at therapeutically relevant concentrations. Further, these mutants showed resistance to imatinib, nilotinib, and crenolanib underscoring the importance of pharmacogenomic investigation. No appreciable difference in sensitivity or resistance profiles was observed between the two mutants. In summary, our findings indicate that these previously uncharacterized p.K385I/L extracellular domain mutations in PDGFRA are oncogenic and represent a pharmacologically actionable target that could be harnessed to increase therapeutic options in the setting of myxoid glioneuronal tumors. Citation Format: Catherine Z. Beach, Romel Somwar, Matthew D. Wood, Monika A. Davare. Characterizing the functional significance of PDGFRAK385I and PDGFRAK385L extracellular domain mutations in the newly defined myxoid glioneuronal tumor. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5012.
Abstract 2836: H2S donors as radiosensitizers for glioblastoma multiforme (GBM)
Authors: Morni Modi, Camila Weber, Qinqin Xu, Kuanling Chen, Ana Cheong, Zachery Nagel, Lynn Harrison
Journal: Cancer Research (2023)

Abstract Glioblastoma multiforme (GBM) is an extremely aggressive CNS cancer in adults. Radiation is a cornerstone therapy but poses high risk of healthy tissue necrosis. Despite maximal treatment, GBM results in death within 15-21 months of diagnosis. These poor statistics suggest the need for a novel therapy. The use of radiosensitizing agents is a novel approach to minimizing radiation mediated healthy tissue necrosis by allowing use of lower doses to achieve comparable cytotoxic effects. Our lab has shown that sodium sulfide (Na2S), a hydrogen sulfide (H2S) donor, selectively kills GBM (T98G) cells while sparing normal human brain endothelial (hCMEC/D3) cells. Na2S also selectively radiosensitizes GBM cells and enhances cell killing with photon or proton radiation. We are currently exploring Diallyl Trisulfide (DATS), another H2S donor, as a radiosensitizing agent and have demonstrated that DATS can kill GBM cells. At a given dose of 2 Gy, radiation alone decreases T98G survival by 10%. With DATS, survival decreases by 70%, suggesting an additive effect. To determine if DATS increases DNA damage mediated cell death, T98G cells were treated with DATS, radiation, or combined DATS + radiation treatment and then analyzed for γH2AX foci, an indicator of double stand breaks (DSB). Our results show that compared to no treatment, DATS increased the number of γH2AX foci per cell by 1.5-fold, by 3-fold with radiation, and by 4-fold with combined DATS + radiation, an additive response. To elucidate the mechanism of increased DNA damage, a novel fluorescence multiplex host cell reactivation (FM-HCR) reporter system was used to assess repair activity of DSBs in live cells. T98G cells pre-treated with DATS were transfected with reporter plasmids containing site-specific lesions, mimicking radiation-like DNA damage. Repair resulted in expression of a fluorescent reporter protein, which was quantitated using flow cytometry. Our results show that DATS did not alter non-homologous end joining (NHEJ) or homologous repair (HR) activity of DSB. However, DATS did alter base excision repair (BER) activity by decreasing repair of abasic lesions and increasing repair 8oxoG lesions. We hypothesize that this attempted BER via simultaneous strand cleavage by AP endonuclease (Ape1) or glycosylase (Ogg1) may lead to build up of repair intermediates, threatening genomic stability and inducing DSB. Pursuing specific DNA repair biochemical assays is required to further understand this effect of DATS on DNA damage and repair inhibition. Citation Format: Morni Modi, Camila Weber, Qinqin Xu, Kuanling Chen, Ana Cheong, Zachery Nagel, Lynn Harrison. H2S donors as radiosensitizers for glioblastoma multiforme (GBM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2836.
Abstract 1129: Targeting tissue-resident macrophage progenitors restores anti-tumor immunity and suppresses tumor growth
Authors: Hui Chen, Marc Paradise, Ryan Shepard, Guangfang Wang, Mark Onaitis, Judith Varner
Journal: Cancer Research (2023)

Abstract Macrophages are innate immune cells that accumulate rapidly in tumors, where they promote immune suppression, tumor growth and resistance to checkpoint inhibitor therapy. As these cells play critical roles in tumor progression, they are the focus of efforts to develop novel cancer therapeutics. Strategies to inhibit macrophage accumulation to suppress tumor growth by blocking their recruitment from circulation have been only partially effective. In this project, we examined the origins of tumor associated macrophages using lineage tracing, flow cytometry, and single cell sequencing. We found that large proportions of macrophages in subcutaneous and genetically engineered mouse tumors do not derive from Ly6C+ or Ly6C- or CCR2+ monocytes. Instead, a large population of CCR2-Ly6C-F4/80hi macrophages that are CD206+MerTK+ are profoundly immune suppressive resident macrophages that arise from a transcriptionally related proliferative progenitor subpopulation rather than by trafficking from the circulation. By comparing gene expression profiles of resident and recruited macrophages in subcutaneous, alveolar, central nervous and renal normal and tumor tissues, we identified generic tissue resident macrophage and recruited signatures that reveal that resident macrophages are more immune suppressive than recruited macrophages and are associated with worse outcomes in cancer patients. Tissue resident macrophages express signatures of Myc-driven proliferation, cholesterol metabolism and profound immune suppression while bone marrow derived macrophages express mixed signatures of inflammation and immune suppression. Genetic and pharmacological inhibition of c-Kit/mCsf1R, cMyc and cyclin-dependent kinases suppressed the expansion of these macrophages, thereby limiting their accumulation in tumors, promoting anti-tumor adaptive immunity and inhibiting tumor progression in mouse models of cancer. We identified a novel cKit/Csf1r/Cdk19 inhibitor that suppressed tissue resident macrophage accumulation and potently inhibited tumor growth. These results identify tissue resident macrophage progenitor cells as key targets for the development of therapeutic strategies to stimulate anti-cancer immunity. Citation Format: Hui Chen, Marc Paradise, Ryan Shepard, Guangfang Wang, Mark Onaitis, Judith Varner. Targeting tissue-resident macrophage progenitors restores anti-tumor immunity and suppresses tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1129.
Abstract 2085: Structural principles of kinase-selectivity drug design
Authors: Mingzhen Zhang, Yonglan Liu, Hyunbum Jang, Ruth Nussinov
Journal: Cancer Research (2023)

Abstract Kinase drug selectivity is one of the main challenges in cancer research. The kinases encoded byhuman genome share the highly similar catalytic kinase domains. As a result, the drug that isdesigned to target one kinase frequently binds to another, leading to the off-target toxicity. Despitethe high structural similarity, the kinase drug pockets at the atomic level are not completelyidentical. We ask that whether there are some inhibitor-accessible geometric features in the kinasepockets that only exist in one kinase but not in all others. To target these unique features in thekinase pockets may help design the kinase drugs with the kinome-wide selectivity. In this work,we describe a transformation invariant protocol (binary network with unsupervised clustering) andperform the kinome-wide structural bioinformatic analysis by integrating the experimental andartificial intelligence (AI)-based kinase structures. The results show that ~ 66.8 % kinases containthe unique features that may distinguish them from all others and the geometric features shared byless than seven other kinases can be found in all the analyzed kinases. We apply the binary networkto EGFR tyrosine kinase and AKT1 serine/threonine kinases, illustrating the potential structuralstrategies to design the high-selectivity kinase drugs. Finally, we develop a cross-platformsoftware, named as KDS (Kinase Drug Selectivity), to achieve the customized real-timevisualization and mutation analysis of the binary networks in the human kinome. Citation Format: Mingzhen Zhang, Yonglan Liu, Hyunbum Jang, Ruth Nussinov. Structural principles of kinase-selectivity drug design [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2085.
Abstract 1971: Understanding the perspectives of Latino smokers on physical activity: A qualitative study
Authors: Francisco Cartujano-Barrera, Edgar Alaniz-Cantu, Maria Valeria Bautista Rojas, Ruthmarie Hernández-Torres, Scott McIntosh, Deborah J. Ossip, Ana Paula Cupertino
Journal: Cancer Research (2023)

Abstract Introduction: Smoking and sedentarism frequently co-occur among Latinos. Evidence suggests that moderate to vigorous physical activity (MVPA) may enhance smoking cessation rates. However, this synergistic phenomenon has not been studied among Latinos, the largest minority group in the U.S. Objective: To understand the perspectives of Latino smokers on physical activity. Methods: Participants were recruited using community-based recruitment strategies. Semi-structured interviews were conducted in English and Spanish with Latino smokers. The Health Belief Model was used as a framework for qualitative theoretical analysis. Results: At baseline, participants’ mean age was 54.9 years old (SD 12.1), 50% of the participants were female, and 85% self-identified as heterosexual or straight. Eight participants (40%) indicated their language of preference as “Only Spanish” and 50% were born in Cuba and the Dominican Republic (25% for each country). Most participants (70%) were light smokers (1-10 cigarettes per day), 35% smoked their first cigarettes within five minutes after waking up, and 50% used menthol cigarettes. We identified perceived benefits (e.g., mood management, weight loss, strategy to quit smoking), susceptibility (e.g., risk of cardiovascular diseases and physical impairment, susceptibility to weight gain), and barriers (e.g., lack of social support, health constraints, and low financial resources) of being physically active. Moreover, we identified cues to action to do physical activity (e.g., being a role model: “⋯I’m going to do it [physical activity] so she [the daughter] can do it too⋯”; spending time with family and friends: “Well, since I have some little nephews and some little nieces... I go with them to the playground⋯”; being outdoors: “⋯go to the parks a lot or go nature walking⋯ being out in the woods⋯ taking all of nature⋯ I would go down to [local towns in New York] on my bicycle⋯”). Conclusion: Multiple perceived factors of being physically active were identified among Latino smokers. These factors provide concrete operational strategies to address smoking cessation and physical activity among Latinos. Further research is needed on how best to integrate these perspectives into smoking cessation interventions. Citation Format: Francisco Cartujano-Barrera, Edgar Alaniz-Cantu, Maria Valeria Bautista Rojas, Ruthmarie Hernández-Torres, Scott McIntosh, Deborah J. Ossip, Ana Paula Cupertino. Understanding the perspectives of Latino smokers on physical activity: A qualitative study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1971.
Abstract 6089: Identification of novel YAP/TAZ pathway regulators in the triple-negative breast cancer cell line MDA-MB231 using single-cell CRISPR screening
Authors: Mareike Berlak, Zuzanna Makowska, Filippos Klironomos, Julia Kuehnlenz, Atanas Kamburov, Andreas Steffen, Martin Lange, Barbara Nicke, Ralf Lesche, Peter Staller, Charlotte Kopitz, Jan Naujoks
Journal: Cancer Research (2023)

Abstract The Hippo signaling cascade is a major pathway that integrates a broad spectrum of mechanosensory signals at the plasma membrane and regulates response via control of cell proliferation, self-renewal, differentiation, and apoptosis. Dysregulation of this pathway has been observed across a range of cancer types and results in an altered activity of its primary downstream effectors, the oncogenic transcription factors YAP/TAZ. For example, both germline and somatic loss-of-function mutations in the tumor suppressor gene NF2, a component of Hippo, induce hyperactivation of YAP/TAZ, transcriptional changes and ultimately result in tumor growth. The Hippo signaling pathway is an attractive target for drug discovery efforts, however, it is highly complex and still incompletely understood. Hence it is indispensable to get a deeper insight into the Hippo - YAP/TAZ signaling axis. To this end, we performed a genome-wide CRISPR knockout screen in the triple-negative breast cancer (TNBC) cell line MDA-MB231 (NF2LOF) expressing a YAP/TAZ reporter construct. We identified both negative and positive regulators of YAP/TAZ in breast cancer cells. In a second step, screening hits were further characterized in a focused single-cell CRISPR screen (Perturb-Seq), aiming at better understanding of the effects on YAP/TAZ activity regulation and downstream effects on gene expression. Here we present the technical details of our screening approaches and the results of perturbing known and novel regulators of YAP/TAZ on single cell level. We discuss the use of Perturb-Seq in the initial validation of hits from genome-wide screens and provide data that may serve as a basis for future drug discovery efforts, seeking for novel and effective treatments for triple-negative breast cancers and other malignancies with Hippo pathway alterations. Citation Format: Mareike Berlak, Zuzanna Makowska, Filippos Klironomos, Julia Kuehnlenz, Atanas Kamburov, Andreas Steffen, Martin Lange, Barbara Nicke, Ralf Lesche, Peter Staller, Charlotte Kopitz, Jan Naujoks. Identification of novel YAP/TAZ pathway regulators in the triple-negative breast cancer cell line MDA-MB231 using single-cell CRISPR screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6089.
Abstract 5343: Evaluating the screened polyphenolics molecules as potential chemosensitizers against the oncogenic signalling proteins in lung cancer
Authors: Swati Arora, Sumit Sheoran, Tanmayee Basu, Naidu Subbarao, Atul Kumar Upadhyay, Sugunakar Vuree
Journal: Cancer Research (2023)

Abstract Background: Lung cancer is the most commonly diagnosed cancer globally. There are numerous agonists and antagonistic treatment interventions available for therapy. However, all of them possess different detrimental consequences in addition to resistance and remission in sufferers. Medicinal plants have traditionally been employed to treat a wide range of ailments and problems. Methodology: A total of 550 flavonoids and small molecules retrieved from literature and databases (Chembl, and PubChem) were analysed for molecular docking, biological activities, ADME, and drug-like properties through SwissADME and PreADMET, Molecular Simulation, and cytotoxicity studies. Simultaneously, review literature is employed to identify the novel protein targets viz. ROS1 (3ZBF) &amp; EGFR (6DUK). Additionally, the crystal structures of the proteins were obtained from PDB and their domains and active sites were predicted using ScanProsite, MOTIF Search, metaPOCKET2, and PrankWeb tools. Finally, the proteins and ligands were energy-minimized using Chimera and open babel tool and subjected to virtual screening and molecular docking using GOLD. Furthermore, the molecular simulation was performed at 100ns by utilizing GROMACS, and cytotoxicity studies were performed by employing the A549 Lung cancer cell line. Results: Diosmin (64.57) and Hesperidin (60.98) had the greatest binding affinity with the identified targets, i.e., ROS1 (3ZBF) and EGFR(6DUK) respectively against Lung Cancer, and remained stable during 100ns of molecular simulation. Furthermore, we have performed cytotoxicity studies on A549 cell lines that show both the compounds have significant anticancer activity and do not affect healthy cells in the range of, i.e., Diosmin (500 µg/ml to 0.024 µg/ml.) and Hesperidin (500 µg/ml to 125 µg/ml). Conclusion: After the analyses, we can conclude that it has the potential to be exploited as a novel therapeutic agent in the treatment of lung cancer.Keywords: Diosmin, Hesperidin, In-silico, A549, Lung Cancer, Simulation Citation Format: Swati Arora, Sumit Sheoran, Tanmayee Basu, Naidu Subbarao, Atul Kumar Upadhyay, Sugunakar Vuree. Evaluating the screened polyphenolics molecules as potential chemosensitizers against the oncogenic signalling proteins in lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5343.